CA2043099A1 - Cyclobutane derivatives - Google Patents

Cyclobutane derivatives

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Publication number
CA2043099A1
CA2043099A1 CA002043099A CA2043099A CA2043099A1 CA 2043099 A1 CA2043099 A1 CA 2043099A1 CA 002043099 A CA002043099 A CA 002043099A CA 2043099 A CA2043099 A CA 2043099A CA 2043099 A1 CA2043099 A1 CA 2043099A1
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CA
Canada
Prior art keywords
cyclobutyl
oxymethyl
group
hydroxymethyl
phosphoryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002043099A
Other languages
French (fr)
Inventor
Yuh-Ichiro Ichikawa
Hiroshi Akaba
Yuka Sugawara
Hideo Sugimura
Kazuhisa Narita
Akira Shiozawa
Kouwa Yamashita
Sayuri Kato
Yukihiro Nishiyama
Kenichi Matsubara
Takemitsu Nagahata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku Co Ltd
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Filing date
Publication date
Application filed by Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Publication of CA2043099A1 publication Critical patent/CA2043099A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to cyclobutane derivatives represented by the following general formula (1) and physiologically acceptable salts thereof:

(1) wherein B represents a nucleic acid base derivative, R1 and R2 independently represent hydrogen atom, dialkyl-aminoacyl group, 1,4-dihydro-1-methylnicotinoyl group or substituted phosphoric acid group, provided that either one of R1 and R2 is a group other than hydrogen atom.
The compounds of this invention exhibit a high oral absorbability and are metabolized in vivo into the compounds of formula (1a). Accordingly, the compounds of this invention are expectedly useful as antiviral agent.

Description

2~3~9 This invention relates to cyclobutane derivatives expectedly useful as medical drugs such as antiviral agent, carcinostatic agent and the like.

BACKGROUND OF THE INVENTION
Compounds represented by the following general formula (la):

Bl (la) HO

wherein B1 represents a nucleic acid base, exhibit an antiviral activity. Particularly, they exhibit a strong activity against herpes simplex virus 1 and 2 (HSV-l, -2), human cytomegalovirus (HCMV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), etc.
Further, there are disclosed a variety of analogues of these compounds (EP 0335355-A2, EP 0358154-A2, EP
0366059-A2).

~3~

SUMMARY OF THE INVENTION
This invention relates to cyclobutane derivatives represented by the following general formula (1) and physiologically acceptable salts thereof:

~ (1) wherein B represents a nucleic acid base derivative and Rl and R2 independently represent hydrogen atom, dialkylaminoacyl group, 1,4-dihydro-1-methylnicotinoyl group or substituted phosphoric acid group, provided that either one of Rl and R2 is a group other than hydrogen atom.
The compounds of this invention have a high oral absorbability and are metabolized in vivo into the above-mentioned compounds (la). Accordingly, the compounds of this invention are expectedly useful as antiviral agent.
In general formula (1), examples of the nucleic acid base derivative B include purine bases, pyrimidine bases and those bases protected by a protect-ing group. As examples of said purine base, the follow-ings can be referred to:

~30~

~/ ~ N </ ~ lH</ ~ J H

</ ~ N <yN ~ N

1 wherein Y represents hydrogen, amino group or halogen such as chlorine, bromine, fluorine and the like, and R3 represents (Cl-C4) alkyl group such as methyl, ethyl, butyl and the like, (Cl-C4) alkoxy-(Cl-C4) alkyl group such as methoxyethyl and the like, or phenyl-substituted (Cl-C4) alkyl group such as benzyl and the like.
As examples of said pyrimidine base, the followings can be referred to:

NH2 o O ~ 0 ~1~

wherein R4 represents hydrogen, tCl-C4) alkyl group such as methyl, ethyl, butyl and the like, phenyl-substituted (Cl-C4) alkyl group such as benzyl and the like, halogenated vinyl group such as 2-bromovinyl, 2-iodovinyl and the like, or halogen such as fluorine, chlorine, bromine and iodine.

~3~l3~
1 In general formula (1), examples of the dialkylaminoacyl group represented by Rl and R2 include di(Cl-C4)alkylamino(Cl-C4)alkylcarbonyl groups such as dimethylaminoacetyl group, diethylaminopropionyl group, dimethylaminobutyryl group and the like, pyrrolidino-propionyl group, and the like. The term "substituted phosphoric acid group" means phosphoric acid groups linked to one or two substituents through intermediation of phosphoric ester bond, and said substituent includes (Cl-C20) alkyl groups such as methyl, ethyl, octyl, octadecyl and the like, substituted alkyl groups and aryl groups including phenyl group, pyridyl group, halogenophenyl groups such as 2-chlorophenyl, 3-chloro-phenyl, 4-fluorophenyl and the like and (Cl-C4) alkyl-phenyl groups such as 4-methylphenyl, (Cl-C4) alkoxy-phenyl group such as 4-methoxyphenyl and the like~ As used herein, the term "substituted alkyl group" means straight or branched chain alkyl groups having an aromatic substituent such as phenyl, 3,4-dihydroxy-phenyl, pyridyl and the like, an amino substituent suchas amino, dimethylamino and the like, a hydroxy sub-stituent, a carboxy substituent, and those substituents into which a protecting group is additionally introduced The preferable group in R2 is phenylphosphoryl group in which the phenyl group is optionally sub-stituted by halogen, (Cl-C4) alkyl group or (Cl-C4) alkoxy group.
As said protecting group, all the groups which 1 are generally used as a protecting group can be used without restriction. As said protecting group, ester type protecting groups such as acyl groups (acetyl, benzoyl and the like) and carbamoyl groups (dimethyl-carbamoyl, diphenylcarbamoyl and the like), silyl typeprotecting groups such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like, ether t.ype pro-tecting groups such as (Cl-C4)alkoxy(Cl-C4)alkyl groups (~ethoxymethyl and the like), tetrahydropyranyl group and the like, and substituted methyl type protect-ing groups having one or more substituted or unsub-stituted phenyl substituent(s) such as benzyl group, 4-methoxybenzyl group, trityl group and the like, can be referred to.
As for the steric configuration of sub-stituents in general formula (1), compounds wherein substituent B and its adjacent hydroxymethyl group are in a trans relationship and the hydroxymethyl group adjacent to substituent B and the other hydroxymethyl group are in a trans relationship are preferable, and (lR,2R,3S) compounds are more preferable.
Said "physiologically acceptable salts"
include alkali metal salts such as sodium salt, potas-sium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, ammonium salt, substituted ammonium salts, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and the like, and salts of organic acids such as acetic acid, fumaric acid, maleic acid, tartaric acid, methane-t~1 ~

1 sulfonic acid and the like.
Next, concrete examples of the compound represented by general formula ~1) will be shown below.
Racemic mixtures of the compounds shown hereinunder are also included in the compounds of general formula (1).
As for salts, no examples are shown herein.
1. 9-[lR,2R,3S)-2-(ethoxyhydroxyphosphoryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine 2. 9-[(lR,2R,3S)-3-(ethoxyhydroxyphosphoryl)-oxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine 3. 9-[(lR,2R,3S)-2,3-bis((ethoxyhydroxy-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 4. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(n-propoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 15~. 9-[(lR,2R,3S)-2-(hydroxymethyl-3-(hydroxy(n-propoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 6. 9-[(lR,2R,3S)-2,3-bis((hydroxy(n-propoxy)-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 7. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(n-octyloxy~phosphoryl)oxymethyl-l-cyclobutyl]-guanine 8. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 9. 9-[(lR,2R,3S)-2,3-bis((hydroxy(n-octyloxy)-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 2510. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(n-octadecyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 11. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octadecyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine ~3~
112. 9-[(lR,2R,3S)-2,3-bis((hydroxy(n-octade-cyloxy)phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 13. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy-(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 514. 9-[(1,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 15. 9-[(lR,2R,3S)-2,3-bis((hydroxy(phenoxy)-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 16. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy-(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 17. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 18. 9-[(lR,2R,3S)-2,3-bis((hydroxy(phenethyloxy)-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 1519. 9-[(lR,2R,3S)-2-(4-dimethylaminobutyryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine 20. 9-[(lR,2R,3S)-3-(4-dimethylaminobutyryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine 21. 9-[(lR,2R,3S)-2,3-bis((4-dimethylamino-butyryl)oxymethyl-l-cyclobutyl]-guanine 22. 9-[(lR,2R,3S)-2-(1,4-dihydro-1-methyl-nicotinoyl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine 23. 9-[(lR,2R,3S)-3-(1,4-dihydro-1-methyl-nicotinoyl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine 24. 9-[(lR,2R,3S)-2,3-bis((1,4-dihydro-1-methylnicotinoyl)oxymethyl)-l-cyclobutyl]-guanine ~3~

1 25. 9-[(lR,2R,3S)-3-(ethoxyhydroxyphoSphoryl)-oxymethyl-2-hydroxymethyl-1-cyclobutyl]-adenine 26. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-propoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 27. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 28. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octadecyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 29. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 30. 9-~(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 31. 9-[(lR,2R,3S)-2-(4-dimethylaminobutyryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-adenine 32. 9-[(lR,2R,3S)-3-(4-dimethylaminobutyryl)-oxymethyl-2-hydroxymethyl-1-cyclobutyl]-adenine 33. 9-[(lR,2R,3S)-2,3-bis((4-dimethylamino-butyryl)oxymethyl)-l-cyclobutyryl]-adenine 34. 9-[(lR,2R,3S)-2-(1,4-dihydro-1-methyl~
nicotinoyl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-adenine 35. 9-[(lR,2R,3S)-3-(1,4-dihydro-1-methyl-nicotinoyl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-adenine 36. 9-[(lR,2R,3S)-2,3-bis((1,4-dihydro-1-methyl-nicotinoyl)oxymethyl)-l-cyclobutyl]-adenine 37. 2-Amino-9-[(lR,2R,3S)-3-(ethoxyhydroxy-phosphoryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-3~

1 purine 38. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-propoxy)-phosphoryl)oxymethyl-l-cyclobutyl]-purine 39. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-purine 40. 2-Amino-9-[tlR,2R,3S)-2-hydroxymethyl-3-hydroxy(n-octadecyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-purine 41. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl~-purine 42. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-purine 43. 2-Amino-9-[(lR,2R,3S)-2-(4-dimethylamino-butyryl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-purine 44. 2-Amino-9-[(lR,2R,3S)-3-(4-dimethylamino-butyryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-purine 45. 2-Amino-9-[(lR,2R,3S)-2,3-bis((4-dimethyl-aminobutyryl)oxymethyl)-l-cyclobutyl]-purine 46. 2-Amino-9-[(lR,2R,3S)-2-(1,4-dihydro-1-methylnicotinoyl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-purine 47. 2-Amino-9-[(lR,2R,3S)-3-(1,4-dihydro-1-methylnicotinoyl)oxymethyl-3-hydroxymethyl-1-cyclo-butyl]-purine 148. 2-Amino-9-[(lR,2R,3S)-2,3-bis((1,4-dihydro-1-methylnicotinoyl)oxymethyl-1-cyclobutyl]-purine 49. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 550. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 51. 9-[(lR,2R,3S)-2,3-bis((hydroxy(2-chloro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 52. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 53. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 54. 9-[(lR,2R,3S)-2,3-bis((hydroxy(3-chloro-phenoxy)phosphoryl)oxymethyl-l-cyclobutyll-guanine 1555. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 56. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 57. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-chloro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 58. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 59. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 2560. 9-[(lR,2R,3S)-2,3-bis((hydroxy(2-fluoro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl~-guanine 61. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-fiuorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 1~2. 9-[(lRI2R,3S)-2-hydroxymethyl~3-(hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl~-guanine 63. 9-[(lR,2R,3S)-2,3-bis((hydroxy(3-fluoro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl~-guanine 564. 9-[(lR,2R,3S~-3-hydroxymethyl-2-~hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 65. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 66. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-fluoro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 67. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-l~cyclobutyl~guanine 68. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 15 69. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methylphenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-guanine 70. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-l~cyclobutyl~-guanine 71. 9-[(:LR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine 72. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methoxy-phenoxy)phosphoryl)oxymethyl3-l-cyclobutyl]-guanine 73. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine i,, ~ 4 174. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl~-adenine 75. 9-[(lR,2R,3S)-2,3-bis((hydroxy(2-chloro-phenoxy)phosphoryl)oxymethyl)-1-cyclobutyl]-adenine 576. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 77. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 78. 9-[(lR,2R,3S)-2,3-bis((hydroxy(3-chloro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine 79. 9-[llR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 80. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 81. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-chloro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine 82. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 83. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 84. 9-[(lR,2R,3S)-2,3-bis((hydroxyt2-fluoro-phenoxy)phos~horyl)oxymethyl)-l-cyclobutyl]-adenine 85. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 2586. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 87. 9-[(lR,2R,3S)-2,3-bis((hydroxy(3-fluoro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine ~3~
188. 9-[(lR,2R,3S)-3-hydroxymethyl-2-~hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 89. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 590. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-fluoro-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine 91. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 92. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 93. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methyl-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine 94. 9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 95. 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-adenine 96. 9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methoxy-phenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-adenine 97. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 98. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-thydroxy(2-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 99. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(2-chlorophenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-purine ~3~ ~3~
1 100. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl)-purine 101. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 102. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-purine 103. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 104. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 105. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(4-chlorophenoxy)phosphoryl)oxymethyl)-l cyclobutyl]-purine 106 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 107. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 108. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(2-fluorophenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-purine 109. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine ~g~ $ ~J ~
1 110. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 111. 2-Amino-9-[(lR,2R,3S)-2,3~bis((hydroxy(3-fluorophenoxy)phosphoryl)oxymethyl)-1-cyclobutyl3-purine 112. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 113. 2-Amino-9-[~lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4~fluorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 114. 2-Amino-9-[(lR,2R,3S~-2,3-bis((hydroxy(4-fluorophenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-purine 115. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 116. 2-Amino-9-[~lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine 117. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methylphenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]-purine 118. 2-Amino-9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-1-cyclobutyl~-purine 119. 2-Amino-9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-purine ~3~
1 120. 2-Amino-9-[(lR,2R,3S)-2,3-bis((hydroxy(4-methoxyphenoxy)phosphoryl)oxymethyl)-l-cyclobutyl]
purine The compounds of this invention represented by general formula (1) can be produced, for example, by reacting a compound represented by general formula (2):

~ (2) wherein R5 and R6 represent hydrogen or a protecting group, provided that at least one of R5 and R6 is hydrogen, and B2 represents a nucleic acid base deriva-tive or a protected nucleic acid base derivative, with acompound represented by the following general formula:

R-OH

or a reactive derivative thereof wherein R represents alkylaminoacyl group, 1,4-dihydro-1-methylnicotinoyl group or substituted phosphoric acid group, and, when a protecting group is present, subse~uently eliminating the protecting group. The compound of the formula R-OH includes a carboxylic acid and phosphoric acid.

~ ~3 ~ 3 ~ ~ ~
1 For example, as shown in the following reaction scheme (l);

HO - ~ R-OH

(2a) (4a) B

RO

HO
(lb) Scheme (1) wherein R5 is a protecting group, B2 is as defined in formula (2), R is as defined above and B is as defined in formula (1), a compound represented by general formula (lb) can be obtained by esterifying the hydroxyl group of compound (2a) with a compound represented by the general formula R-OH such as, for example, a phos-phate compound and a condensing agent such as dicyclo-hexylcarbodiimide (DCC), water-soluble carbodiimide (WSC) or the like at a temperature of -20C to 50C in a solvent capable of dissolving compound (2a), preferably a polar solvent such as DMF and the like, and thereafter eliminating the protecting group by an appropriate method such as solvolysis (hydrolysis, ammonolysis or the like).

f~ ~ ~

1 In the same manner as above, a compound of the following general formula (lc):

~5> ( lc ) RO

wherein B and R are as defined above, can be obtained from a compound of formula (2) wherein R6 is a protect-ing group and R5 is a hydrogen atom, and a compound ofthe following general formula (ld):

RO ~

~ (ld) wherein B and R are as defined above, can be obtained from a compound of formula (2) wherein R5 and R6 are both hydrogen atom.
When R is a substituted phosphoric acid group, there is no limitation upon the protecting group.
However, when R is alkylaminoacyl group or nicotinoyl group, the use of non-~carboxylic acid) type protecting group such as 4,4'-dimethoxytrityl group and the like is more preferable than the use of carboxylic acid type protecting group such as acetyl group.

~Q~3~9 1 Next, experiment examples will be presented below to demonstrate the strong antiviral activity and excellent oral absorbability of the compounds of this invention.

Experiment Example 1 Antiviral activity against Herpes simplex 1 virus (HSV-l) which is a DNA virus was tested by the following method.

(Method 1) Vero cells (originated from kidney cells of African Green Monkey) were cultured in MEM medium to which 10% bovine embryo serum had been added. A cell suspension adjusted to a concentration of 200,000 cells/ml was spread onto a 96 wells plate (COSTAR) and cultured for 24 hours so that the cells became confluent. To the medium drawn out was added HSV-l virus, and it was infected for one hour. Then, the virus fluid was drawn out and cultured for about 72 hours in a fresh medium containing agents. The alive cells were stained with a staining solution containing Neutral Red and absorbance at a wavelength of 546 nm ~As46) was measured to evaluate the cytopathic effect (CPE).
CPE inhibition (~) was calculated according to the following equation:

CPE inhibition ~ A546 (drug treatment) - AS46 (virus control)~
1 0 0 x 1 --~
A546 ~cell alone) - A546 ~virus control) 1 and a quantity of sample enouyh for 50~ inhibition of the CPE due to virus was taken as IC50 (~g/ml).
The results are summarized in Table 1.

Experimantal Example 2 Antiviral activity against human cytomegalo-virus (HCMV) which is a DNA virus was tested by the following method.

(method 2) Confluent monolayers of human embryonic fibroblasts in plastic dishes (diameter: 35 mm) were infected with 100 to 150 plaque forming units of HCMV.
After an l-hour adsorption period at 37C, the cultures were overlaid with 2 ml of 0.5% agarose in Eayle's minimum essential medium containing 3~ fetal calf serum and various concentrations of drugs. The cultures infected with HCMV were fixed and stained at 9 or 10 days after infection. The second agarose overlay conta ning appropriate concentrations of drugs was added 5 days after infection. Plaque numbers were counted by using a dissecting microscope at x20 magnification. The antiviral activities of drugs were expressed in terms of 2~d~

1 median effective concentrations (EC50) which were defined as the drug concentrations that reduced the number of plaques to 50%. The results are summarized in Table 1.

Experimantal Example 3 Antiviral activity against hepatitis B virus ~HBV~ which is a DNA virus was tested by the following method.

(Method 3) The test was done by using a cell line, HB611, that was established by transfection and continuously produces HBV-like particles [Proc. Natl. Acad. Sci. USA, 84, 444-449, 1987]. HB611 cells were maintained in Dulbecco's modified Eagle medium (Gibco) supplemented with 10% fetal bovine serum (Gibco), 100 ~g/ml of streptomycin, 100 IU ml of benzyl penicillin (Gibco) and 200 ~g/ml of geneticin (Gibco) at 37C in 5% C02-95%
air.
The cells were seeded in 24-well plate (Corning) at a density of 3 x 104 cells/well, using 1.0 ml of the medium. After 2 days of incubation, the medium was replaced with the same medium containing the test compound. The cells were incubated for a further 15 days, during which time the medium containing the drug was exchanged every three days. The cells were then harvested and cellular DNA was prepared [Virology, h ~ 9 1 169, 213-216, 1989], and digested with restriction enzyme Hind III (Takara Shuzo Co., Ltd.). An aliquot (2-3 ~g) was electrophoresed in 1.5% agarose gel, followed by blotting onto a nylon membrane Hybond-N+
according to Southern [J. Mol. Biol., 98, 503-517, 1975]. The filter was hybridized to random primed 3zp labeled HBV DNA probe, and washed twice with 2x standard saline citrate containing 0.1% SDS at 65C for 30 min.
It was then autoradiographed, and the results were analyzed using a densitometric analyzer (Shimadzu, Chromatoscana S930).
To quantitatively evaluate the inhibitory activity of the compounds, we measured the band areas S, Dl, D2 (S, Dl and D2 represent intracellular free HBV
DNA dexived from replicative intermediates) and I
(represents chromosomally integrated HBV DNA) by densitometric analyzer, and calculated the inhibition percentage as follows:

Inhibition (%) =

( Sdrug + Dldrug + D2drug ) /Idrug ( SCont ~ DlCont + D2cont j /ICont J

The results are summarized in Table 1.
In table 1, antiviral activity is represented by 50~ inhibition doses (IDso) on HBV DNA synthesis.

~ 22 -~3~

Table 1 Anti-HSV-l, anti-HCMV, and anti-HBV
activities of the compounds of this invention _ Compound (~g/ml)(~g/ml) (~g/ml) No. HSV-l HCMV HBV
.._ ._ 1.13 1-3 ca. 0.1 53 1.22 1-3 0.1-1.0 56 0.699 1-3 0.1-1.0 1.13 1-3 0.1-1.0 68 1.26 0.1-1 0.1-1.0 71 0.873 0.1-1 0.1-1.0 1 Experiment Example 4 Oral absorbability of compounds of this invention were tested according to the following method.

(Method 4) Male CDFl mice (6-8 weeks in age) (Japan Charles Liver Co.) were used. Each substance to be tested was dissolved into physiological salt solution, and its 75 ~M/kg dosage (0.1-0.5 ml/10 g dosage) was administered orally or intravenously. Ten minutes, thirty minutes, one hour and 3 hours after the administration, blood was taken from 2-3 heads of mice by means of an injection tube previously treated with heparin, and the blood was centrifuged at 3,000 rpm for l lO minutes to obtain a plasma. To 200 ~e of the plasma was added 9-[2-hydroxy-3-hydroxymethylcyclobutan-1-yl]-guanine (2 ~g/10 ~e H2O) as an internal standard. After diluting it with 4 ml of water, it was washed with 2 ml of water by the use of Ceppack Clg Cartridge (Millipore Waters Co.). It was eluted with 5 ml of methanol, concentrated to dryness, re-dissolved into 200 ~e of water, and then subjected to HPLC to measure the concentration of 9-((lR,2R,3S)-2,3-bis(hydroxymethyl)-1-cyclobutyl) guanine (Compound la, wherein Bl=9-guanyl), from which maximum concentration (Cmax), time of maximum concentration ~Tmax) and the area under the concentration curve (AUC) were determined.

(Conditions of HPLC) Column: Cosmosil 5C18-P (Nacalai Tesque, 250 mm x 4.6 mm, i.d.) Solvent: O.lM citric acid (pH 4) :
acetonitrile : methanol = 50 : 2 : l Flow rate: 1 ml/min.
Wavelength: 254 nm The results of this experiment are summarized in Table 2.

~ 3 !~

Table 2 Concentration of Compound la (Bl = 9-guanyl) in plasma after administration of compounds of this invention ..
Com- Intravenous injection Oral administration pound Cmax Tmax AUC Cmax Tmax AUC
. .
(~g/ml) (~g-hr/ml) (~g/ml) (~g hr/ml) 13 4.607 10' 2.962 1.683 30' 1.122 14 9.485 10' 5.076 2.460 30' 2.262 5.912 10' 3.177 1.057 30' 1.526 53 5.208 10' 3.228 0.760 30' 1.405 56 5.167 10' 3.167 0.928 10' 1.762 6.332 10' 6.373 1.345 30' 1.712 68 6.552 10' 4.116 1.358 30' 1.754 71 6.700 10' 4.393 1.355 10' 1.678 1 As shown above, the compounds of the present invention change by metabolism in living body to the compound la (Bl=9-guanyl), which is expected to be useful against many viral deseases, described in EP0358154 A2.
Since the compounds of this invention repre-sented by general formula (1) have a strong antiviral activity and a high oral absorbability and a high solubility in water, they are expected to be useful against many viral diseases such as herpes labialis, herpes genitalis, herpes zoster, and infections of herpes simplex virus 1 and 2 ~HSV-l, -2), varicella zoster virus (VZV), cytomegalo virus (CMV) and Ebstein-bar virus (EBV), as well as against viral hepatitis, viral diseases of the respiratory organs, viral diseases of the digestive organs, AIDS, ATL and the like.

P ~ 3 'J

1 Further, they are expectedly useful as an anticancer agent, too.
In putting the compounds of this invention which have been obtained in the above-mentioned manner to use as an antiviral agent or an anticancer agent for mammal, they can be administered orally, intravenously or percutaneously. Its dose is usually 0.1-500 mg/kg/day, though it may vary depending on the symptoms and age of patient and method of administration. The compounds of this invention are administered in the form of a preparation produced by mixing them with an appropriate vehicle. As the form of the preparation, tablet, granule, fine granule, powder, capsule, injection, cream, suppository and the like can be adopted. Content of the compound of this invention in such preparations is about 0.1 to 99%.
Next, production of the compounds of this invention will be illustrated more concretely-by way of the followin~ examples.

Example 1 Production of 9~[(lR,2R,3S)-3-(ethoxyhydroxy-phosphoryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-~uanine (Compound No. 2) Under a stream of argon gas, 9-[(lR,2R,3S)-2-acetoxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (57.4 mg, 0.19 mmole) and ethyl dihydrogen phosphate (0.4 mmole) are dissolved into pyridine (2 ml), and the pyridine is distilled off under reduced pressure. The 1 residue is dissolved into pyridine (2 ml), dicyclohexyl-carbodiimide (DCC) (248 mg, 1.2 mmoles) is added, and the mixture is stirred at room temperature for 2 days.
Water (2 ml) is added to the reaction mixture and stirred for one hour, after which volatile substances are distilled off under reduced pressure. After adding an additional quantity of water and distilling off volatile substances under reduced pressure, water 14 ml) is added and the mixture is heated at 100C for one hour. After cooling it, concentrated aqueous ammonia (2 ml) is added and stirred overnight. Solvent is distilled off from the reaction mixture under reduced pressure, water is added to the residue, and insoluble matter is filtered off. The filtrate is purified by DEAE Sephadex column chromatography (water 0.5M NaCl) and de-salted by means of a de-salting apparatus (Microacylizer G-l, mfd. by Asahi Kasei Kogyo) to obtain sodium salt of 9-[(lR,2R,3S)-3-~ethoxyhydroxyphos-phoryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine (79 mg).
NMR (200 MHzFT, D2O) ~:
1.18 (3H, dt, J=0.73, 7.1 Hz), 2.12-2.38 (2H, m), 2.53 (lH, m), 2.79 (lH, m), 3.67 (2H, d, J=5.9 Hz), 3.79-3.94 (4H, m), 4.46 (lH, m), 7.92 (lH, s).
HRMS (FAB):
Calcd for [C13HlgNsO6PNa~H]+; 396.1049.
Found; 396.1054 1 Example 2 Production of 9-[(lR,2R,3S)-2-(ethoxyhydroxy-phosphoryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (Compound No. 1) The reaction and after treatment of Example 1 are repeated, except that the 9-[(lR,2R,3S)-2-acetoxy-methyl-3-hydroxymethyl-1-cyclobutyl]-guanine is replaced with 9-[(lR,2R,3S)-3-acetoxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine, to obtain 9-[(lR,2R,3S)-2-(ethoxyhydroxyphosphoryl)-oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (quantitative yield).
NMR (2~0 MHzFT, D2O) ~:
1.01 (3H, dt, J=0.74, 7.1 Hz), 2.06 (lH, m), 2.24 (lH, m), 2.55 (lH, m), 2.85 (lH, m), 3.58-3.74 (4H, m), 3.92 (2H, t, J=5.8 Hz), 4.55 (lH, m), 7.92 (lH, s)O
HRMS (FAB):
Calcd for [Cl3HlgN5O6PNa+H]+; 396.1049.
Found; 396.1036.

Example 3 Production of 9-[(lR,2R,3S)-2,3-bis((ethoxy-hydroxy-phosphoryl)oxymethyl)-l-cyclobutyl]-guanine (Compound No. 3) The reaction and after treatment of Example 1 are repeated, except that the 9-[(lR,2R,3S)-2-acetoxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine is replaced with 9-[(lR,2R,3S)-2,3-bis(hydroxymethyl)-1-,vL.;L3~

1 cyclobutyl]-guanine and ethyl dihydrogen phosphite is used in an amount of 5 equivalents and DCC is used in an amount of 10 equivalents. Thus, 9-[(lR,2R,3S)-2,3-bis((ethoxyhydroxyphosphoryl)oxymethyl)-l-cyclobutyl]-guanine (17%) is obtained.
NMR (200 MHzFT, D20) ~:
1.04 (3H, dt, J=0.74, 7.0 Hz), 1.18 (3H, dt, J=0.73, 7.1 Hz), 2.25 (lH, m), 2.35 (lH, m), 2.53 (lH, m), 3.00 (lH, m), 3.70 (2H, quint, J=7.1 Hz), 3.79-4.00 (6H, m), 4.59 (lH, m), 7.98 (lH, s).
HRMS (FAB):
Calcd for [C15H23N509P2Na2+H~+; 526.0845.
Found; 526.0869.

Example 4 The following compounds are obtained by repeating the reaction and after treatment of Examples 1-3, except the reacted reagents are altered.
9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy(n-octyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 7) NMR (200 MHzFT, DMSO-d6) ~:
0.83 (3H, diff. t, J=6.4 Hz), 1.05-1.33 (lOH, m), 1.33-1.55 (2H, m), 2.03 (lH, m), 2.19 (lH, m), 2.33 (lH, m), 2.84 (lH, m), 3.30-3.85 (6H, overlapped with other peak), 4.49 (lH, 2~3~9 1 apparent q, J=8.4 Hz), 4.97 (lH, brs), 6.94 (2H, brs), 7.83 tlH, s).
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 8) NMR (200 MHzFT, DMSO-d6) ~:
0.84 (3H, diff, t, J=6.6 Hz), 1.06-1.37 (lOH, m), 1.37-1.605 (2H, m), 2.05-2.60 (3H, m), 2.90 (lH, m), 3.30-3.90 (6H, overlapped with other peak), 4.20 (lH, brs), 4.41 (lH, apparent q, J=8.4 Hz), 6.83 (2H, brs), 7.78 (lH, s).
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(n-octadecyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 11) NMR (200 MHzFT, DMSO-d6) ~:
0.85 (3H, diff, t), 1.10-1.40 (30H, m), 1.45-1.67 (2H, m), 2.10-2.65 (3H, m), 2.84 ( lH, m), 3.34-4.06 (6H, overlapped with other peak), 4.49 (lH, apparent q, J=8.4 Hz), 6.42 (2H, brs), 7.84 (lH, s), 10.54 (lH, brs).
9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy-(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 13) NMR (200 MHzFT, DMSO-d6) ~:
1.92-2.24 (2H, m), 2.31 (lH, m), 2.85 (lH, m), 3.40-3.55 (2H, overlapped with other peak), 3.68-3.95 (2H, m), 4.46 (lH, apparent q, J=8.4 ~ 3'~

1 Hz), 4.82 (lH, brt, J=4.7 Hz), 6.71 (2H, brs), 7.05-7.24 (5H, m), 7.80 (lH, s), 10.92 (lH, brs).
9-[(lR,2R,3S)-3-hydroxymethyl-2-(hydroxy-(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 16) NMR (200 MHzFT, DMSO-d6) ~:
2.01 (lH, m), 2.16 (lH, m), 2.33 (lH, m), 2.71-2.88 (3H, m), 3.40-3.75 (4H, overlapped with other peak), 3.82 (2H, q J=7.2 Hz), 4.43 (lH, apparent q, J=8.5 Hz), 6.93 (2H, brs), 7.06-7.36 (5H, m), 7.87 (lH, s).
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenethyloxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (compound No. 17) NMR (200 MHzFT, DMSO-d6) ~:
2.04-2.41 (3H, m), 2.73-2.93 (3H, m), 3.33-3.60 (2H, overlapped with other peak), 3.67-3.80 (2H, m), 3.87 (2H, q, J=7.0 Hz), 4.43 (lH, apparent q, J=8.5 Hz), 4.95 (lH, brs), 6.87 (2H, brs), 7.11-7.35 (5H, m), 7.81 (lH, s), 11.13 (lH, brs).
9-[(lR,2R,3S)-2,3-bis((4-dimethylamino-butyryl)oxymethyl)-l-cyclobutyl]-guanine (Compound No.
21) NMR (200 MHzFT, D2O) ~:
1.62-1.80 (2H, m), 1.88-2.07 (2H, m), 2.11-2.70 (7H, m), 2.76 (6H, s), 2.83 (6H, s), j t~ ~

1 2.86-3.05 (3H, m), 3.06-3.18 (2H, m), 4.21 (2H, d, J=5.3 Hz), 4.24 (2H, d, J=6.3 Hz), 4.53 (lH, apparent q, J=8.8 Hz), 7.94 (lH, s).

Example 5 Production of 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(2-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-guanine (Compound No. 50~
under a steam of argon gas, 9-[(lR,2R,3S)-2-acetoxy-methyl-3-hydroxymethyl-1-cyclobutyl]-guanine (153.7 mg, 0.5 mmole) and (2-chlorophenyl) dihydrogen phosphate (219 mg, 1.05 mmoles) are dissolved into pyridine (5 ml), and the pyridine is distilled off under reduced pressure. The residue is dissolved into pyridine (5 ml), dicyclohexylcarbodiimide (DCC) (650 mg, 3.15 mmoles) is added, and the mixture is stirred at room temperature for 16 hours. Water (5 ml) is added to the reaction mixture and stirred for one hour, after which volatile substances are distilled off under reduced pressure. Further, water (10 ml) is added and volatile su~stances are distilled off under reduced pressure. Then, water (10 ml) is added, the mixture is heated at 100C for one hour and cooled, and then concentrated aqueous ammonia (5 ml) is added and the resulting mixture is ~tirred at room temperature overnight. Solvent is distilled off from the reaction mixture under reduced pressure, water is added to the residue, and the insoluble matter is filtered off. The 3 ~
1 filtrate is purified by DEAE Sephadex column chromato-graphy twater, 0.5M NaCl) and further purified by HP-20 column chromatography (water, 50% methanol) to obtain sodium salt of 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(2-chlorophenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-guanine (181 mg, 76%).
NMR (200 MHzFT, D2O) ~:
2.10 (lH, m), 2.22 (lH, m), 2.42 (lH, m), 2.56 (lH, m), 3.58 (2H, d, J=5.7 Hz), 3.99 (2H, diff. t, J=5.1 Hz), 4.31 (lH, apparent q, J=8.4 Hz), 6.92 (lH, t, J=7.7 Hz), 7.12 (lH, dt, J=1.6 Hz, 7.8 Hz), 7.20-7.32 (2H, m), 7.75 (lH, s).
HRMS (FAB):
Calcd for [C17HlgClNsO6PNa+H]+; 478.0659.
Found; 478.0649.

Example 6 The following compounds are obtained by repeating the reaction and after treatment of Example 5, except that the reacted reagents are altered.

9[-(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(3-chlorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 53) (Yield: 79%) NMR (200 MHzFT, D2O) ~:
2.00-2.33 (2H, m), 2.42 (lH, m), 2.59 (lH, m), 3.58 (2H, d, J=5.6 Hz), 3.96 (2H, diff. t, 1 J-5.1 ~z), 4.31 (lH, apparent q, J=8.4 Hz) 6.92-7.20 (4H, m), 7.75 (lH, s).
H~MS (FAB~:
Calcd for ~C17HlgClN5O6PNa+H]+; 478.0659.
Found; 478O0668~
9~[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxyl4-chlorophenoxy)phosphoryl)oxymethyl~ yclobutyl~-guanine (Compound No. 56) (Yield: 78~) NMR (200 MHzFT, D2O) ~:
1.95-2.31 (2H, m), 2.33-2.54 ~2H, m), 3.57 (2HI d, J=5.5 Hz), 3.94 (2H, diff. t, J=5.0 Hz)~ 4.29 (lH, m), 6.97-7.14 (4H, m), 7.75 (lH, s~.
HRMS (FAB):
Calcd for [Cl7HlgClN5O6PNa+H]+; 478.0659.
Found; 478.0625.
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4 fluorophenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 65) (Yield: 73%) NMR (200 MHzFT, D2O) ~:
2.02-2.33 (2H, m), 2.37-2.68 (2H, m), 3.57 (2H, d, J=5.8 Hz), 3.96 (2H, diff. t~ J=5.2 Hz), 4.33 (lH, apparent ql J=8.5 Hz), 6.90 (2H, diff. t, J=8.8 Hz), 7.00-7.11 (2H, m), 7.78 (lH, s).
H~MS (FAB):
Calcd for [C17Hlg~N5O6PNa+H]+; 462.0955.
Found; 462.0915.

i ~ 3 ~ ~ v , ! ~

1 9-[~lR,2~,3S) ~-hydroxymethyl-3 (hydroxy(4-methylphenoxy)phosphoryl)oxymethyl-l-cyclobutyl~-guanine (Compound No. 68) (Yield: 74~) NMR (200 MHzFT, D2O) ~:
2 . 06 ( 3H, S ), 1. 96-2.30 (2~, m), 2.32-2 D 53 (2H, m), 3~55 (2H, d, J-5O5 Hz), 3.88-3.97 (2H, m), 4.28 ~lH, apparent q, J=8.4 Hz), 6.94 (4H, s), 7.75 (lH, s).
HRMS (FAB):
Calcd for [ClgH22NsO6PNa+H]+; 458.1205.
Found; 458.1188.
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(4-methoxyphenoxy)phosphoryl~oxymethyl-1-cyclobutyl]-guanine (Compound No. 71) (Yield: 85~) NMR (200 MHzFT, D2O) ~:
1.96-2.32 (2H, m), 2.32-2.52 (2H, m), 3.57 (2H, d, J=5 r 4 Hz), 3.62 (3H, s), 3.89-3.98 (2H, m), 4.30 (lH, apparent q, J=8.5 Hz), 6.70 (2HI d, J=8.9 Hz)~ 7.03 (2H, dd, J=1.05, 8.9 Hz), 7.77 (1~, s).
HRMS (FAB):
Calcd for [Cl8H22N5O7PNa+H]+; 474.1155.
Found; 474.1168.

Example 7 Production of 9 [(lR,2R,3S)-3-(4-dimethylaminobutyryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine (Compound No. 20) ~3~7~9 1 Under a stream of argon gas, N2- ( 4, 4 ' -dimethoxytrityl)-9-[(lR,2R,3S)-2-(4,4'-dimethoxy-trityl~oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (360 mg, 0.41 mmole), 4-(dimethylamino)-butyric acid hydrochloride (138.7 mg, 0.83 mmole) and 4-(dimethyl-amino)-pyridine (10.1 mg, 0.08 mmole) are dissolved into DMF (4 ml), and then the DMF is distilled off under reduced pressure. The residue is dissolved into DMF ( 4 ml). Pyridine (0.17 ml, 2.07 mmoles) and dicyclohexyl-carbodiimide (DCC) (170.8 mg, 0.83 mmole) are addedthereto, and the resulting mixture is stirred at room temperature overnight. After adding water (4 ml) to the reaction mixture and stirring the mixture for one hour, ethyl acetate and water are added and insoluble matter is filtered off. The filtrate is extracted with ethyl acetate. The extract layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, volatile substances are distilled off under reduced pressure.
80~ acetic acid (30 ml) is added to the residue and stirred overnight. After distilling off the volatile substances from the reaction mixture under reduced pressure, water is added and the water is distilled off.
Water is added to the residue and the resulting mixture is washed with ether, after which pH value is adjusted to 9. The solution thus obtained is purified by CM
Sephadex column chromatography (water, 0.5M NaCl) and then de-salted by the use of a de-salting apparatus ~3~g~3 1 (Microacylizer G-l, mfd. by Asahi Kasei Kogyo) to obtain 9-[(lR,2R,3S)-3-(4-dimethylamino-butyryl)oxymethyl-2-hydroxymethyl-l-cyclobutyl]-guanine hydrochloride (52.0 mg, 30.3%)-9-[(lR,2R,3S)-3-(4-dimethylaminobutyryl)oxy-methyl-2-hydroxymethyl-1-cyclobutyl]-guanine:
NMR (200 MHzFT, D2O) ~:
1.88-2.07 (2H, m), 2.07-2.83 (4H, m~, 2.49 (2H, t, J=7.3 Hz), 2.83 (6H, s), 3.07-3.18 (2H, m), 3.68 (2H, d, J=5.9 Hz), 4.21 (2H, d, J=5.5 Hz), 4.48 (lH, apparent q, J=8.6 Hz), 7.92 (lH, s).

Example 8 Production of 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenoxy)phosphoryl)oxymethyl-l-cyclobutyl]-guanine (Compound No. 14) Under a stream of argon gas, 9-[(lR,2R,3S)-2-acetoxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (92.3 mg, 0.3 mmole) and phenyl dihydrogen phosphate (107.9 mg, 0.62 mmole) are dissolved into pyridine (4 ml), and the pyridine is distilled off under reduced pressure. The residue is dissolved into pyridine (4 ml), dicyclohexylcarbodiimide (DCC) (376.7 mg, 1.8 mmoles) is added thereto, and the mixture is stirred at room temperature for 7 days. After adding water (5 ml) to the reaction mixture and stirring it for one hour, volatile substances are distilled off under reduced 2~3~

1 pressure. Further, water (10 ml) is added and volatile substances are distilled off under reduced pressure, after which water (8 ml) is added. The resulting mixture is heated at 100C for one hour, and then cooled. Then, concentrated aqueous ammonia (4 ml) is added and stirred at room temperature overnight. After distilling off the volatile substances from the reaction mixture under reduced pressure, water is added to the residue and insoluble matter is filtered off. The filtrate is purified by DE~E Sephadex column chromato-graphy (water, 0.5M NaCl) and then additionally purified by ~P-20 column chromatography (water, 50~ methanol) to obtain sodium salt of 9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy(phenoxy)phosphoryl)-oxymethyl-l-cyclobutyl]-guanine (57.7 mg, 43%).
9-[(lR,2R,3S)-2-hydroxymethyl-3-(hydroxy-(phenoxy)-phosphoryl)oxymethyl-l-cyclobutyl]-guanine:
NMR (200 MHzFT, DMS-d6) ~:
2.05-2.35 (3H, m), 2.81 (lH, m), 3.40-3.55 (2H, overlapped with other peak), 3.81-3.91 (2H, m), 4.41 (lH, apparent q, J=8.2 Hz), 4.92 (lH, brs), 6.87 (2H, brs), 7.09-7.28 (5H, m), 7.75 (lH, s).

Referential Example 1 Production of 9-[(lR,2R,3S)-2-acetoxymethyl-3-hydroxymethyl-l-cyclobutyl]-guanine and 9-[(lR,2R,3S)-3-acetoxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine 1 Under a stream of argon gas, 9-[(lR,2R,3S)-2,3-bis(hydroxymethyl)-1-cyclobutyl]-guanine (500 mg, 1.85 mmoles) is dissolved into DMF (10 ml) at 40 to 50C, and the DMF is distilled off under reduced pressure. The residue is dissolved into DMF (25 ml).
Pyridine (0.30 ml, 3.7 mmoles) and acetic anhydride (0.17 ml, 1.85 mmoles) are added, and the mixture is stirred at room temperature for 3 days. After distilling off volatile substances from the reaction mixture under reduced pressure, the product is separated and purified b~ HP-20 column chromatography (water, 70%
methanol) to obtain:
9-~(lR,2R,3S)-2-acetoxymethyl-3-hydroxymethyl-l-cyclobutyl]-guanine ~127 mg, 22%):
NMR (200 MHzFT, CD30D) ~:
1.96 (3H, s), 2.19 (lH, m), 2.28-2.59 ~2H, m), 3.01 (lH, m), 3.68 (2H, d, J=5.3 Hz), 4.15-4.32 t2H, m), 4.59 (lH, apparent q, J=8.8 Hz), 7.86 (lH, s).
and 9-[(lR,2R,3S)-3-acetoxymethyl-2-hydroxymethyl-l-cyclobutyl]-guanine (150 mg, 26%);
NMR (200 MHzFT, DMSO-d6) ~:
2.03 (3H, s), 2.02-2.50 (3H, m), 2.75 (lH, m), 3.42-3.51 (2H, m), 4.07-4.24 (2H, m), 4.48 (lH, apparent q, J=8.3 Hz), 4.69 (lH, diff. t, J=5.3 Hz), 6.40 (2H, brs), 7.89 (lH, s), 10.57 (lH, brs).

3~
1 Referential Example 2 Production of N2-(4,4'-dimethoxytrityl)-9-[(lR,2R,3S)-2-(4,4'-dimethoxytrityl)oxymethyl-3-hydroxymethyl-l-cyclobutyl]-guanine In an atmosphere of argon gas, 9- (lR,2R,3S)-3-acetoxymethyl-2-hydroxymethyl-1-cyclobutyl -guanine (265 mg, 0.86 mmole) is dissolved into DMF (2 ml) at 40 to 50C, and the DMF is distilled off under reduced pressure. The residue is dissolved into DMF (5 ml).
Triethylamine (0.54 ml, 3.9 mmoles) and 4,4'-dimethoxy-trityl chloride (877 mg, 2.59 mmoles) are added thereto, and the resulting mixture is stirred at room temperature overnight. After distilling off volatile substances from the reaction mixture under reduced pressure, the residue is purified by silica gel column chromatography (methylene chloride : methanol = 40 : 1) to obtain N2-(4,4'-dimethoxytrityl)-9-[(lR,2R,3S)-2-(4,4'-dimethoxy-trityl)-oxymethyl-3-acetoxymethyl-1-cyclobutyl]-guanine (449 mg, 57%)-The N2~(4,4'-dimethoxytrityl)-9-[(lR,2R,3S)-2-(4,4'-dimethoxytrityl)oxymethyl-3-acetoxymethyl-1-cyclobutyl]-guanine (447 mg, 0.49 mmole) obtained above is dissolved into a mixture consisting of methanol (5 ml) and methylene chloride (1 ml), potassium carbonate (76 mg, 0.55 mmole) is added under cooling with ice, and the mixture is stirred at room temperature overnight.
After adding 0.2M phosphate buffer to the reaction mixture, it is extracted with ethyl acetate. The ~30~
1 extract solution is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (methylene chloride : methanol =
30 : 1) to obtain N2-(4,4'-dimethoxytrityl)-9-[(lR,2R,3S)-2-(4,4'-dimethoxytrityl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (364 mg, 85~).

NMR (200 MHzFT, CDCl~
1.97-2.11 (2H, m), 2.27 (lH, m), 3.09 (lH, m), 3.26-3.62 (3H, m), 3.74 (6H, s), 3.76 (6H, s), 4.12 (lH, m), 6.42 (lH, brs), 6.80 (8H, diff.
d, J=8.8 Hz), 7.14-7.40 (19H, m), 9.10 (lH, brs).

Claims (10)

1. A cyclobutane derivative represented by the following general formula (1) and physiologically acceptable salt thereof:

(1) wherein B represents a nucleic acid base derivative, R1 and R2 independently represent hydrogen atom, dialkyl-aminoacyl group, 1,4-dihydro-1-methylnicotinoyl group or substituted phosphoric acid group, provided that either one of R1 and R2 is a group other than hydrogen atom.
2. A cyclobutane derivative of Claim 1, wherein B
is a purine base linked at the 9-position.
3. A cyclobutane derivative according to Claim 2, wherein said purine base is guanine.
4. A cyclobutane derivative according to Claim 1, wherein R1 or R2 is an aryl-substituted phosphoric acid group.
5. A cyclobutane derivative according to Claim 4, wherein said aryl-substituted phosphoric acid group is a phenylphosphoryl group in which the phenyl group is optionally substituted by halogen, C1-C4 alkyl group or C1-C4 alkoxy group.
6. A cyclobutane derivative according to Claim 1, wherein B is guanine, R1 is hydrogen atom and R2 is hydroxy(phenoxy)phosphoryl group.
7. 9-[(1R,2R,3S)-2-(hydroxymethyl-3-(hydroxy-(phenoxy)phosphoryl)oxymethyl-1-cyclobutyl]-guanine.
8. An antiviral agent against a virus comprising a yclobutane derivative represented by the following general formula (1) and physiologically acceptable salt thereof:

(1) wherein B represents a nucleic acid base derivative, R1 and R2 independently represent hydrogen atom, dialkyl-aminoacyl group, 1,4-dihydro-1-methylnicotinoyl group or substituted phosphoric acid group, provided that either one of R1 and R2 is a group other than hydrogen atom.
9. An antiviral agent according to Claim 8, wherein B is guanine, R1 is hydrogen atom and R2 is a phenylphosphoryl group in which the phenyl group is optionally substituted by halogen, C1-C4 alkyl group or C1-C4 alkoxy group.
10. An antiviral agent according to Claims 8 or 9, wherein the virus is herpes simplex virus, cytomegalo virus or hepatitis B virus.
CA002043099A 1990-05-24 1991-05-23 Cyclobutane derivatives Abandoned CA2043099A1 (en)

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